Immune checkpoint inhibitor‐induced myasthenia gravis, myocarditis, and myositis: A case report

Key Clinical Message Immune checkpoint inhibitors can rarely lead to occurrence of myositis, myocarditis, and myasthenia gravis (MG). Early recognition and multidisciplinary management are crucial for optimal outcomes. Vigilance for overlapping toxicities is essential in patients receiving combination immunotherapy. Abstract The use of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, but it is associated with immune‐related adverse events (IRAEs) affecting various organ systems. The simultaneous occurrence of MG, myocarditis, and myositis highlights the complex nature of IRAEs. Early recognition and comprehensive multidisciplinary management are crucial for optimal patient outcomes. We present a unique case report of a 76‐year‐old male patient with advanced melanoma who developed concurrent myositis, myocarditis, and MG while receiving combination immunotherapy with Nivolumab and Ipilimumab. This case underscores the significance of recognizing and addressing the “Terrible Triad” of IRAEs in patients receiving ICIs. Healthcare providers should maintain a high index of suspicion for overlapping toxicities and promptly initiate appropriate interventions.

observed in patients treated with ICIs, especially PD-1 inhibitors, with an incidence ranging from 0.12%-0.2%. 3 The combination of anti-CTLA-4 (Cytotoxic T-Lymphocyte-Associated Antigen 4) and anti-PD-1 (Programmed Death 1) therapies has been identified as a significant risk factor for this terrible triad of MG, Myocarditis, and Myositis, with ipilimumab and nivolumab combination therapy carrying a 4.74-fold higher risk compared to nivolumab alone. 2Here, we present a unique case report of a 76-year-old male patient with advanced melanoma who developed concurrent myositis, myocarditis, and MG while receiving combination immunotherapy with Nivolumab and Ipilimumab.

| CASE HISTORY/EXAMINATION
A 76-year-old male patient with a medical history of coronary artery disease, treated with percutaneous intervention (PCI) and stent placement 13 years ago, as well as hypertension, hyperlipidemia, diabetes, hyperthyroidism (managed with partial thyroidectomy), and a previous history of melanoma treated with excision and immunotherapy, presented with a progressive onset of shortness of breath over a period of 6 days.The patient had received his most recent dose of immunotherapy, comprising 100 mg of Ipilimumab and 300 mg of Nivolumab, 3 weeks prior to his presentation.Initially, the shortness of breath occurred during exertion but gradually worsened to affect routine daily activities.The patient also experienced weakness in the facial muscles but denied symptoms such as difficulty breathing when lying down (orthopnea), sudden episodes of breathing difficulty at night (paroxysmal nocturnal dyspnea), chest pain, or dizziness.
Upon arrival at the emergency department, the patient's vital signs were stable.A physical examination revealed mild weakness in the facial muscles, while the remainder of the examination did not yield any significant findings.

AND TREATMENT)
Laboratory tests showed a rise in troponin levels from an initial value of 3.74 ng/mL-5 ng/mL, along with elevated liver enzymes, myoglobin, creatinine, and white blood cell count as summarized in Table 1.However, the electrocardiogram did not reveal any ST-segment or T-wave changes as in Figure 1.Additionally, the computed tomography angiography of the chest did not detect a pulmonary embolism or parenchymal lung disease.A bedside echocardiogram revealed preserved left ventricular ejection fraction without significant wall motion abnormalities or valvular heart disease.Serial electrocardiograms did not display significant changes compared to the admission electrocardiogram.
The patient was initiated on a heparin drip due to persistent shortness of breath and elevated troponin levels.Subsequent coronary angiography revealed 99 percent stenosis in the mid-left anterior descending artery (LAD) as in Figure 1, for which percutaneous transluminal coronary angioplasty, shockwave lithotripsy, and placement of a drug-eluting stent were performed.The patient's dyspnea did not improve despite coronary stenting; troponin levels remained elevated, likely due to myocarditis.While in the hospital, the patient developed diffuse weakness, most notably in the extra ocular, facial, nasopharyngeal, neck flexor, respiratory muscles, and all four extremities, with proximal weakness being more pronounced.Orientation, superficial sensation, and coordination of the upper extremities remained largely intact.
The patient's computed tomography angiography of the chest revealed vocal cord paralysis.Consultation with neurology and oncology services suggested IRAEs from checkpoint inhibitors, possibly leading to myasthenia crisis and myocarditis.Positive tests for MG-specific antibodies confirmed the suspicion, while lumbar puncture ruled out other conditions.

| RESULT AND OUTCOME
Respiratory distress worsened despite increased oxygen support, leading to elective intubation for airway protection.Empirical treatment with methylprednisolone was initiated on the fourth day of hospitalization.Recurrent wide-complex tachycardia was unresponsive to cardioversion and adenosine.The patient received amiodarone, lidocaine, and later procainamide.Renal and liver function deteriorated, requiring continuous venovenous hemodiafiltration (CVVHDF).Despite resuscitative efforts, the patient experienced multiple cardiac arrests and could not be revived and died on the 13th day of admission.

| DISCUSSION
ICIs are a class of monoclonal antibodies that target specific inhibitory receptors in the immune system, namely CTLA-4, PD-1, and PD-L1 (programmed cell death ligand 1). 4 These receptors are predominantly found on T cells, a type of immune cell.By blocking the interaction between these receptors, ICIs enhance the immune response against cancer cells, thereby aiding in their elimination.Ipilimumab, approved in 2011, was the first immune-related therapy to be authorized for the treatment of melanoma, followed by approvals for renal cell carcinoma and colorectal cancer. 5Since then, additional ICIs have been approved for various malignancies.
IRAEs are associated with disrupted T-cell tolerance, increased levels of preexisting autoantibodies, and elevated inflammatory cytokines.This aberration leads to the activation of T-cells, which mistakenly target healthy tissues, resulting in the development of IRAEs. 6lthough the precise cause of myocarditis associated with ICIs remains uncertain, it is hypothesized that there may be shared antigens between tumors and cardiac tissue contributing to this immune reaction. 7The medical literature reports several other IRAEs, such as hepatitis, myositis, colitis, thyroiditis, MG, nephritis, pneumonitis, rhabdomyolysis, hypophysitis, neuritis, polyneuropathy, conjunctivitis/uveitis, syndrome of inappropriate antidiuretic hormone, encephalitis, and Stevens-Johnson syndrome. 8In our case, the patient exhibited clinical manifestations suggestive of myositis, myocarditis, MG, and nephritis.
Our case report highlights the significant impact of the "Terrible Triad"-immune checkpoint inhibitor-induced MG, myocarditis, and myositis.Some studies found that patients with all three toxicities had a notably higher risk of death than those with MG alone, MG and myositis, or myocarditis alone. 2Additionally, MG tended to manifest earlier than other neurotoxicities after immunotherapy.Interestingly, a separate study on ICI-related myocarditis revealed that myositis and MG were the most common coexisting IRAEs. 1 It is worth noting that the diagnosis of ICI-related myositis can be challenging due to oculomotor weakness, which may complicate the identification of MG. 9 ICI-related myocarditis is a relatively rare but potentially fatal complication, with reported incidence rates ranging from 0.04% to 1.14%.Its mortality rate is significantly high, ranging from 25% to 50%. 10 Combination therapy with ICIs increases the risk of developing myocarditis and the associated mortality.The clinical presentation of myocarditis can vary.Severe cases may present with life-threatening symptoms such as cardiogenic shock and severe arrhythmias.
On the other hand, milder cases can resemble viral myocarditis, exhibiting symptoms similar to acute coronary syndrome, new-onset heart failure, or chronic heart failure.Patients may also present with pericardial effusion, with or without pericarditis.It is crucial to differentiate myocarditis from other conditions like coronary artery disease (CAD) or other causes of heart failure, especially considering that cancer patients often have underlying CAD.Diagnostic tests are essential to confirm and manage suspected ICI cardiotoxicity.The probability of ICI-associated myocarditis increases when patients present with concomitant IRAEs, particularly MG and myositis. 11merican Society of Clinical Oncology (ASCO) has developed guidelines for managing IRAEs, including myocarditis.These guidelines categorize myocarditis into four severity grades, [1][2][3][4] with Grades 1 representing mild cases and 4 indicating the most severe cases. 6According to the guidelines, patients with suspected myocarditis should undergo a comprehensive evaluation, including cardiac biomarkers, electrocardiogram (ECG), chest x-ray, echocardiogram, and cardiac MRI.While these tests provide valuable information, an endomyocardial biopsy is the gold standard diagnostic test for myocarditis. 12Invasive coronary angiography may also rule out coronary artery disease in patients with elevated troponin levels.When immune-related myocarditis is suspected, it is crucial to promptly discontinue ICIs and initiate high-dose glucocorticoid therapy.The ASCO clinical practice guidelines recommend a steroid tapering regimen over 4-6 weeks, although the optimal duration for tapering remains uncertain. 6In cases where glucocorticoids alone are insufficient, alternative immunomodulatory treatments such as intravenous immunoglobulin, mycophenolate, infliximab, anti-thymocyte globulin, plasmapheresis, alemtuzumab, or abatacept may be considered. 7It is important to note that the management of immune-related myocarditis should be tailored to each patient and their specific clinical circumstances.

| CONCLUSION
Prompt recognition and discontinuation of the ICI, along with the use of high-dose glucocorticoids, were crucial in managing the IRAEs.The response to treatment varied among the different conditions, highlighting the need for individualized approaches.This case report underscores the importance of early detection and intervention in IRAEs associated with ICIs.Treatment decisions should be made in collaboration with a multidisciplinary team, including oncologists, cardiologists, and other relevant specialists.Continued research is necessary to enhance our understanding and management of these complex immune-related complications.

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I G U R E 1 Mid-LAD showing 99 percent stenosis.